Soluble adenylyl cyclase‐mediated cAMP signaling and the putative role of PKA and EPAC in cerebral mitochondrial function

Abstract

Mitochondria produce the bulk of the ATP in most cells, including brain cells. Regulating this complex machinery to match the energetic needs of the cell is a complicated process that we have yet to understand in its entirety. In this context, 3′,5′‐cyclic AMP (cAMP) has been suggested to play a seminal role in signaling‐metabolism coupling and regulation of mitochondrial ATP production. In cells, cAMP signals may affect mitochondria from the cytosolic side but more recently, a cAMP signal produced within the matrix of mitochondria by soluble adenylyl cyclase (sAC) has been suggested to regulate respiration and thus ATP production. However, little is known about these processes in brain mitochondria, and the effectors of the cAMP signal generated within the matrix are not completely clear since both protein kinase A (PKA) and exchange protein activated by cAMP 1 (EPAC1) have been suggested to be involved. Here, we review the current knowledge and relate it to brain mitochondria. Further, based on measurements of respiration, membrane potential, and ATP production in isolated mouse brain cortical mitochondria we show that inhibitors of sAC, PKA, or EPAC affect mitochondrial function in distinct ways. In conclusion, we suggest that brain mitochondria do regulate their function via sAC‐mediated cAMP signals and that both PKA and EPAC could be involved downstream of sAC. Finally, due to the role of faulty mitochondrial function in a range of neurological diseases, we expect that the function of sAC‐cAMP‐PKA/EPAC signaling in brain mitochondria will likely attract further attention.

Elevated cAMP Protects against Diclofenac-Induced Toxicity in Primary Rat Hepatocytes: A Protective Effect Mediated by the Exchange Protein Directly Activated by cAMP/cAMP-Regulated Guanine Nucleotide Exchange Factors

“…We show that a AC-cAMP-EPAC1 and a PDE-cAMP-EPAC2 domain play a role in maintaining the mitochondrial membrane potential during diclofenacinduced toxicity. Although the role of EPAC in the mitochondria has been described previously in neurons (Jakobsen, Lange and Bak, 2019), this is the first time we show similar results in primary rat hepatocytes. The exact mechanism for the protective effect of EPAC against diclofenac-induced toxicity remains to be elucidated.…”

“…The second messenger 3',5'-cyclic adenosine monophosphate (cAMP) is synthesized by catalytic conversion of ATP by plasma membrane-bound adenylyl cyclase (pmAC) on hormonal activation of G s coupled receptors and by Ca 2+ and bicarbonate-sensitive soluble adenylyl cyclase (sAC) (Wiggins et al, 2018;Rahman et al, 2013). cAMP is degraded by phosphodiesterases (PDE) -a superfamily of enzymes comprised of over 100 isoforms, and the only enzymes that degrade cAMP, thereby dictating the local level of cAMP at various subcellular sites (Jakobsen, Lange and Bak, 2019;Maurice et al, 2014). PDEs are highly expressed in the liver and are in part localized in various organelles including the mitochondria, with PDE1A, PDE2, PDE3B, PDE8A and PDE11A being the most prominent isoforms in human and rat liver (Lakics, Karran and Boess, 2010;Azevedo et al, 2014;Monterisi et al, 2017).…”

“…Recent evidence suggests that EPAC plays a major role in metabolic pathways previously thought to be controlled by PKA (Insel et al, 2012). Indeed, evidence has shown that in addition to PKA, EPAC alters mitochondrial function in both brain cells and cardiomyocytes, thereby suggesting that EPAC, as a downstream target of cAMP, is a novel target for the treatment of neurological diseases and the prevention of cardiovascular ailments (Wang et al, 2016;Jakobsen, Lange and Bak, 2019;Fazal L et al, 2017).…”

Cell Communications among Microorganisms, Plants, and Animals: Origin, Evolution and Interplays

“…channel-receptors letting in specific ions [111,112]; receptors acting by direct catalysis (receptors with intrinsic enzymatic activity, i.e. protein kinase activity [113,114], or phosphatase activity [115], or guanylate cyclase activity [116,117]) ; receptors acting through recruitment of various downstream intracellular effectors (G proteins [118][119][120][121][122][123][124][125], adenylate cyclases [126][127][128], phospholipases C [129][130][131], soluble protein kinases [132][133][134][135][136][137], methyltransferases [138], proteases [139][140][141][142]…”

Cell Communications among Microorganisms, Plants, and Animals: Origin, Evolution and Interplays

“…channel-receptors letting in specific ions [118,119]; receptors acting by direct catalysis (receptors with intrinsic enzymatic activity, i.e. protein kinase activity [120,121], or phosphatase activity [122], or guanylate cyclase activity [123,124]; receptors acting through recruitment of various downstream intracellular effectors (G proteins [125][126][127][128][129][130][131][132], adenylate cyclases [133][134][135], phospholipases C [136][137][138], soluble protein kinases [139][140][141][142][143][144], methyltransferases [145], proteases [146][147][148][149] downstream partners are generally concentrated at the level of lipid rafts [150] or primary cilium in metazoan [84,151]. The downstream signaling pathways and their evolution have been thoroughly described in a recent comprehensive review [152] Many hormones are released in a pulsatile manner, and the frequency of their pulsatile secretion often governs the efficacy of their signaling.…”